Transcription Factors Activate Genes through the Phase-Separation Capacity of Their Activation Domains

Cell. 2018 Dec 13;175(7):1842-1855.e16. doi: 10.1016/j.cell.2018.10.042. Epub 2018 Nov 15.


Gene expression is controlled by transcription factors (TFs) that consist of DNA-binding domains (DBDs) and activation domains (ADs). The DBDs have been well characterized, but little is known about the mechanisms by which ADs effect gene activation. Here, we report that diverse ADs form phase-separated condensates with the Mediator coactivator. For the OCT4 and GCN4 TFs, we show that the ability to form phase-separated droplets with Mediator in vitro and the ability to activate genes in vivo are dependent on the same amino acid residues. For the estrogen receptor (ER), a ligand-dependent activator, we show that estrogen enhances phase separation with Mediator, again linking phase separation with gene activation. These results suggest that diverse TFs can interact with Mediator through the phase-separating capacity of their ADs and that formation of condensates with Mediator is involved in gene activation.

Keywords: activation domain; gene activation; mediator; phase separation; transcription; transcription factor.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • HEK293 Cells
  • Humans
  • Mice
  • Mouse Embryonic Stem Cells / cytology
  • Mouse Embryonic Stem Cells / metabolism*
  • Octamer Transcription Factor-3 / genetics
  • Octamer Transcription Factor-3 / metabolism*
  • Protein Domains
  • Receptors, Estrogen / genetics
  • Receptors, Estrogen / metabolism*
  • Transcriptional Activation / physiology*


  • Octamer Transcription Factor-3
  • Pou5f1 protein, mouse
  • Receptors, Estrogen